Categories: Muscle phene

Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 603034 (trait) , 603033 (gene)

Links to MONDO diseases:

• MONDO:0011281: congenital myasthenic syndrome 5

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2014

Species-specific name: Congenital myasthenic syndromes

Species-specific symbol: CMS

Mapping: Having access to only two affected members of a single family, Rinz et al. (2014) were not able to conduct a GWAS to map this disorder. Instead they examined haplotype inheritance in the region of 18 comparative candidate genes (based on genes with known causal mutations for various types of CMS in humans), using relevant SNPs from the 173,662 SNPs in the Illumina CanineHD Infinium BeadChip, in the two affected littermates, five normal littermates and the two normal (but related) parents. Only one candidate gene (COLQ; officially known as LOC608697) [on chromosome CFA23] showed concordant inheritance.

Molecular basis: Subsequent sequencing by Rinz et al. (2014) of the primary candidate gene (COLQ or LOC608697; see Mapping section above) revealed a causal mutation as "a variant in exon 14 (c.1010T>C) that results in the substitution of a conserved amino acid (I337T) within the C-terminal domain. Both affected puppies were homozygous for this variant, and 16 relatives were heterozygous, while 288 unrelated Labrador Retrievers and 112 dogs of other breeds were wild-type." Sequencing the functional candidate gene COLQ in four affected Golden Retriever puppies from a single breeder enabled Tsai et al. (2020) to identify "a point mutation that predicts an amino acid substitution (G294R). The primary COLQ transcript was absent from affected muscle samples. All affected puppies were homozygous for the mutation, which was not detected outside this GR family or in other breeds."

Genetic engineering: Unknown
Have human generated variants been created, e.g. through genetic engineering and gene editing

Clinical features: Affected puppies present with a history of generalised skeletal muscle weakness and fatigue with an onset in the first weeks to months of life (Mignan et al., 2020). As reported by Rinz et al. (2014): "Neurological examination was consistent with a generalized neuromuscular disease with marked short-strided tetraparesis that worsened with exercise. Postural reactions were preserved with the exception of hopping which was diminished in all limbs when the puppies were made to bear full weight. Spinal reflexes including the patellar, cranial tibial, and flexor withdrawals were reduced in all limbs. A pyridostigmine bromide challenge resulted in worsening of muscle weakness." Clinical signs often progress despite treatment, and most reported cases have resulted in death or euthanasia of affected puppies (Mignan et al., 2020). [IT thanks DVM student Lily Cai for contributions in April 2022]

Pathology: As a result of the COLQ mutation, acetylcholinesterase is anchored to the basal lamina of the neuromuscular junction (NMJ). Measurement of the compound muscle action potential through electrodiagnostic testing after repetitive nerve stimulation shows a decremental response, which is consistent with failure of neuromuscular transmission (Tsai et al., 2020). A NMJ antibody testing for acetylcholinesterase is negative (Mignan et al., 2020). [IT thanks DVM student Lily Cai, who provided the basis of this contribution in April 2022]

Breeds: Golden Retriever (Dog) (VBO_0200610), Labrador Retriever (Dog) (VBO_0200800).
Breeds in which the phene has been documented. For breeds in which a likely causal variant has been documented, see the variant table below

Associated gene: